ABSTRACT

The glucocorticoid receptor (GR) is an evolutionally conserved nuclear receptor superfamily protein that mediates the diverse actions of glucocorticoids as a ligand-dependent transcription factor. This receptor is a protein that shuttles from the cytoplasm to the nucleus upon binding to its ligand glucocorticoid hormone, where it modulates the transcription rates of glucocorticoid-responsive genes positively or negatively. Tremendous efforts have been made to reveal the molecular signaling actions of the GR, including intracellular shuttling, transcriptional regulation and interaction with other intracellular signaling pathways. Glucocorticoids are essential for both maintenance of the resting state and the stress response, and are pivotal in the treatment of many disorders, including autoimmune, inflammatory, allergic, and lymphoproliferative diseases. Thus, pathologic or therapeutic implications of the GR, including genetic alterations in the human GR gene, disease-associated GR regulatory molecules, and development of GR ligands with selective GR actions, are of great importance. This chapter provides an overview on such GR-related research activities. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Glucocorticoids are steroid hormones secreted by the adrenal glands. They are important for the maintenance of basal and stress-related homeostasis by acting as end products of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis (1). Glucocorticoids regulate a variety of biologic processes and exert profound influences on many physiologic functions (2,3). In pharmacologic doses, glucocorticoids are used as potent immunosuppressive agents in the therapeutic management of many inflammatory, autoimmune and lympho-proliferative diseases (4). At the cellular level, the actions of glucocorticoids are mediated by an intracellular receptor protein, the glucocorticoid receptor (GR) (its gene name is “nuclear receptor subfamily 3, group C, member 1: NR3C1”), which belongs to the steroid/sterol/thyroid/retinoid/orphan receptor superfamily of nuclear transactivating factors with over 200 members in general and over 40 in mammals currently cloned and characterized across species (5). Human GR consists of 777 amino acid residues (5). GR is ubiquitously expressed in almost all human tissues and organs including neural stem cells (6). GR functions as a hormone-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes, which probably represent 3-10% of the human genome and can be influenced by the ligand-activated GR directly or indirectly (7).

EVOLUTION OF GR

Nuclear hormone receptors (NRs) form a highly conserved protein family observed even in simple metazoans. They are phylogenically differentiated into 7 subfamilies under the evolutional selection pressure, and are still active in the current human population (8). GR is a member of the steroid hormone receptor (SR) subfamily (subfamily 3) of NRs. This receptor family of vertebrates consists of six evolutionarily related SRs: two for estrogens (estrogen receptor (ER) a and ERβ) and one each for androgens (androgen receptor: AR), progestins (progesterone receptor: PR), glucocorticoids (GR), and mineralocorticoids (mineralocorticoid receptor: MR) (Figure 1). These steroid receptors are also categorized as type I receptors, based on their functional characteristics, such as cytoplasmic localization in the absence of ligand with association to the heat shock proteins, homo-dimerization and recognition of their target DNA sequence (see below), while the other NRs belong to type II to IV (5).

Figure 1.

Steroid hormone receptors (SRs: class I receptors) and their homologies expressed as percent identity to the protein sequence of human GR. AR; androgen receptor, ER: estrogen receptor, ER: estrogen receptor, GR; glucocorticoid receptor, MR: mineralocorticoid receptor, PR-A: progesterone receptor-A. Modified from (9).

SRs evolved in the chordate lineage after the separation of deuterostomes and protostomes, prior to or at the base of the Cambrian explosion about 540 million years ago (10,11) (Figure 2A). The receptor phylogeny suggests that two serial gene duplications of an ancestral SR gene occurred before the divergence of lamprey and jawed vertebrates (Figure 2B). The first gene duplication (duplication #1 in Figure 2B) created an estrogen receptor (ER) and a 3-ketosteroid receptor, whereas the second duplication (duplication #2 in Figure 2B) of the latter gene produced a corticoid receptor and a receptor for 3-ketogonadal steroids (androgens, progestins, or both). Therefore, the ancestral vertebrates (e.g., lamprey) had three SRs: an estrogen receptor (ER), a receptor for corticoids (corticosteroid receptor: CR) and a receptor that bound androgens, progestins or both (ancestral PR). At some later time within the gnathostome lineage, each of these three receptor genes were duplicated again (duplications #3, #4 and #5 in Figure 2B) to yield the six SRs currently found in jawed vertebrates: the ER creating ERa and ERβ, CR yielding the GR and MR, and the 3-ketogonadal steroid receptor (ancestral PR) producing the PR and AR. Therefore, the genome of ‘higher’ vertebrates is thought to be the result of three genome duplication events that occurred early in chordate evolution (10,12). Although the timing of these events is not entirely clear, it is most likely that the first 2 duplications occurred before the lamprey-gnathostome divergence and one after (10,13).

Figure 2.

Evolution of SRs including GR. A: Appearance of the SR member receptors through evolution of the chordate lineage. The first ancestral SR, which is close to the current ER, appeared ~540 million years ago. At lamprey, 3 receptors, ER, PR and CR, emerged. From the ray-finned fishes, all SR members, ER, PR, AR, GR and MR, appeared. Modified from (14). B: Phylogeny of the SR family genes. Current human SRs including GR were generated through several gene duplications (shown as orange squares). Appearance of the ancestral (Anc) SR1, SR2 and CR are shown with arrows in the phylogeny tree. Blue lines indicate the lamprey-gnathostome divergence. Modified from (10).

The GR and its closest family member MR, both descend from duplication of the ancestral CR (AncCR) gene, and emerged in the vertebrate lineage approximately 450 million years ago (12,15) (Figure 2B). The GR is activated by cortisol, while the MR is activated by aldosterone in tetrapods and by deoxycorticosterone (DOC) in teleosts. The MR is also sensitive to cortisol, though considerably less so than to aldosterone and DOC (12,15). Like the MR, the AncCR is sensitive to aldosterone, DOC and cortisol, indicating that the specificity of GR for cortisol is evolutionarily derived (12,15).

To determine how the preference of the GR for cortisol evolved, Ortlund et al. identified substitutions that occurred during the same period as the shift in GR function (16). Using maximum likelihood phylogenetics, he revealed that GR retained AncCR’s sensitivity to aldosterone, DOC and cortisol, from the common ancestor of all jawed vertebrates, but the GR from the common ancestor of bony vertebrates obtained a phenotype like that of the current GRs that respond only to cortisol. These findings indicate that the specificity of GR for cortisol evolved during the interval between these two speciation events, approximately 420 to 440 million years ago (16). Amino acid substitutions found in the modern GR compared to AncGR are not a consequence of the direct introduction of corresponding nucleotide changes, but supported by permissive mutations that enabled the intermediate receptor to tolerate insertion of the final substitutions (17).

Teleosts, one of the 3 subgroups of ray-finned fishes that covers most of the living fishes today, underwent an additional gene duplication event about 350 million years ago (18). Thus, all fishes that belong to this subclass, including carp and rainbow trout, have 2 GR genes (GR1 and 2 in rainbow trout). However, zebrafish has only one GR gene in contrast to the other teleost families, because this species lost the 2^nd GR gene sometime during the last 33 million years (18).

STRUCTURE OF THE HUMAN GR GENE AND PROTEIN

All SRs including GR display a modular structure comprised of five to six regions (A-F): the amino-terminal A/B region, also called immunogenic or N-terminal domain (NTD), and the C and E regions, which correspond to the DNA- (DBD) and ligand-binding (LBD) domains, respectively (Figure 3). D region represents the hinge region (HR), while F region is located in the C-terminal end of the NRs with high variability. GR does not have a F region. The GR cDNA was isolated by expression cloning in 1985 (19). The human GR gene consists of 9 exons and is located in the long arm of the chromosome 5 (5q31.3) in an inverse orientation and spanning ~160 kbs. Alternative splicing of the human GR gene in exon 9 generates two highly homologous receptor isoforms, termed a and b. These are identical through amino acid 727, but then diverge, with human GRa having an additional 50 amino acids and human GRb having an additional, nonhomologous 15 amino acids (20). The molecular weights of these receptor isoforms are 97 and 94 kilo-Dalton, respectively. Human GRa is expressed virtually in all organs and tissues, resides primarily in the cytoplasm, and represents the classic glucocorticoid receptor that functions as a ligand-dependent transcription factor. Human GRb, also expressed ubiquitously, does not bind glucocorticoid agonists and functions as a dominant negative receptor for GRa-induced transcriptional activity (see Section 7. THE SPLICE VARIANT GR-beta ISOFORM) (21).

Figure 3.

Genomic and complementary DNA and protein structures of the human (h) GR with its functional distribution, and the isoforms produced through alternative splicing. The hGR (NR3C1) gene consists of 10 exons. Exon 1 is an untranslated region (UTR), exon 2 encodes for NTD (A/B), exon 3 and 4 for DBD (C), and exons 5-9 for the hinge region (D) and LBD (E). GR does not have an F region in contrast to the other steroid hormone receptors. The GR (NR3C1) gene contains two terminal exons 9 (exon 9 and 9) alternatively spliced to produce the classic GR and the nonligand-binding GR isoform. C-terminal gray-colored domains in GR and GR show their specific portions. Locations of several functional domains are also indicated. AF-1 and -2: activation function-1 and -2; DBD; DNA-binding domain; HD: hinge region; LBD: Ligand-binding domain; NTD: N-terminal domain, NL1 and 2: Nuclear translocation signal 1 and 2.

The N-terminal domain (NTD) of GRa contains a major transactivation domain, termed activation function (AF)-1, which is located between amino acids 77 and 262 of the human GRa (22,23). AF-1 belongs to a group of acidic activators, such as VP16, nuclear factor of kB (NF-kB), p65 and p53, contains four a-helices, and plays an important role in the communication between the receptor and molecules necessary for the initiation of transcription, including coactivators, chromatin modulators and basal transcription factors [RNA polymerase II, TATA-binding protein (TBP) and a host of TBP-associated proteins (TAFIIs)] (24). GRa AF-1 is relatively unfolded at the basal state, while it forms a significantly complex helical structure in response to binding to cofactors, such as TBP and p160 coactivators (25,26). TBP-induced conformational change in AF-1 facilitates association of this domain to a p160 coactivator (27).

The DNA-binding domain (DBD) of the human GRa corresponds to amino acids 420-480 and contains two C4-type zinc finger motifs through which GRa binds to specific DNA sequences, the glucocorticoid-responsive elements (GREs) (28,29). The DBD is the most highly conserved domain throughout the NR family. It has two similar zinc finger modules, each nucleated by a zinc ion coordination center held by four cysteine (C) residues and followed by a-helix (Figure 4A). The N-terminal’s first a-helix lies in the major groove of the double-stranded DNA, while the C-terminal part of the second a-helix is positioned over the minor groove (Figure 4B).

Figure 4.

Structure of GR DBD and its interaction with DNA GRE. A: Zinc finger structures in DBD of hGR. Numbered eight cysteine (C) residues chelate Zn2+ to form two separate finger structures. Red-colored amino acid residues form -helical structures. Box with bold line indicates lever arm, while that with dashed line shows D-box. Modified from (30). B: 3-Dimensional model of the physical interaction between the GR DBD and DNA GRE. The N-terminal’s first -helix of the GR DBD lies in the major groove of the double-stranded DNA, while the C-terminal part of the second -helix is positioned over the minor groove. The image was created and donated by Dr. D.E. Hurt (National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD). Box with bold line indicates lever arm, while that with dashed line shows D-box. Modified from (30).

The ligand-binding domain (LBD) of the human GRa corresponds to amino acids 481-777, binds to glucocorticoids, and plays a critical role in the ligand-induced activation of GRalpha. The crystal structure of the GRalpha LBD was successfully analyzed by using a point mutant containing a single replacement of phenylalanine at amino acid 602 by serine, and is comprised of 12 a-helices and 4 small β-sheets that fold into a three-layer helical domain (31) (Figure 5). Helices 1 and 3 form one side of a helical sandwich, while helices 7 and 10 form the other side. The middle layer of the helices (helices 4, 5, 8, and 9) is present in the top but not the bottom half of the protein. This arrangement of helices creates a cavity in the bottom half of the LBD, which is surrounded by helices 3, 4, 11 and 12, and functions as a ligand-binding pocket (31-33). Interaction of the LBD with the heat shock protein (hsp) 90 contributes to the maintenance of the protein structure that allows LBD to associate with ligand. Ligand-binding induces a conformational change in the LBD and allows GRa to communicate with several molecules, such as importin a of the nuclear import system, components of the transcription initiation complexes and other transcription factors that mediate the ligand-dependent actions of GRa. The LBD also contains one transactivation domain, termed AF-2. The activity of AF-2 is ligand-dependent.

Figure 5.

Structure of the GR LBD. The GR consists of 12 -helices and 4 small β-sheets that fold into a three-layer helical domain. Helices 1 and 3 form one side of a helical sandwich, while helices 7 and 10 form the other side. The middle layer of helices 4, 5, 8, and 9 are present in the top but not in the bottom half of the protein, thus creating a ligand-binding pocket (shown as yellow star) in the bottom half of the LBD, surrounded by helices 3, 4, 11 and 12. The image was created with the MacPyMOL software using 3K22 of the RCSB Protein Data Bank (PDB) (http://www.rcsb.org/pdb/home/home.do).

TRANSCRIPTIONAL AND TRANSLATIONAL REGULATION OF GR ISOFORMS

As described above, the human GR gene expresses two mRNAs through alternative use of exon 9a and 9b, and produces two splice variants. The human GRa mRNA further expresses multiple isoforms by using at least 8 alternative translation initiation sites (34) (Figure 6). Since human GRb shares a common mRNA domain that contains the same translation initiation sites with human GRa (19), the human GRb variant mRNA seems also to be translated through the same initiation sites to a similar host of b isoforms. They are produced by ribosomal leaky scanning and/or ribosomal shunting from their alternative translation initiation sites located at amino acids 27 (GRa-B), 86 (GRa-C1), 90 (GRa-C2), 98 (GRa-C3), 316 (GRa-D1), 331 (GRa-D2) and 336 (GRa-D3), C-terminally from the classic translation start site (1: for the GRa-A) (34). Thus, they have different lengths of NTDs but the same DBDs and LBDs. Compared to GRa-A, GRa-C2 and GRa-C3 isoforms have stronger transcriptional activities on a synthetic GRE-driven promoter, while GRa-D1, GRa-D2 and GRa-D3 demonstrate weaker activities (34). GRa-B and GRa-C1, however, possess transcriptional activities similar to that of GRa-A (34). Absence of AF-1 in GRa-D isoforms may explain their reduced transcriptional activity, while ~100 amino acids (particularly 3 polar amino acids) located in the N-terminal portion of AF-1 appear to support increased transcriptional activity of GRa-C isoforms (35). All human GRa isoforms translocate into the nucleus in response to ligand, while they are differentially distributed in the cytoplasm and/or the nucleus in the absence of ligand and display distinct transactivation or transrepression patterns on global gene expression examined by cDNA microarray analyses (34). Such isoform-specific transcriptional activity is in part explained by their distinct chromatin modulatory activity, which is evident in the different potencies of the translational isoforms to induce apoptosis in T-cell Jurkat cells (36).

Figure 6.

GR isoforms produced through alternative splicing or use of different translational initiation sites. The human GR (NR3C1) gene contains two terminal exons 9 (9alpha and 9beta) alternatively spliced to produce the classic GR (GRalpha-A) and GRbeta-A. C-terminal dark yellow-colored domains in GRalpha-A and GRbeta-A show their specific portions. Using at least 8 different translation initiation sites located in NTD, the human GR (NR3C1) gene produces multiple GR isoforms termed A through D (A, B, C1-C3 and D1-D3) with distinct transcriptional activities on glucocorticoid-responsive genes. Since GRalpha and GRbeta share a common mRNA domain that contains the same translation initiation sites, the GRbeta variant mRNA appears to be also translated through the same initiation sites and to produce 8 isoforms with different lengths of NTD. Modified from (20,37). AF-1 and -2: activation function-1 and -2; DBD; DNA-binding domain; HD: hinge region; LBD: Ligand-binding domain

Translational Human GRa isoforms are differentially expressed in various cell lines, tissues and at different developmental stages (34). For example, GRa-D isoforms are predominant in immature bone marrow-derived dendritic cells (DCs), while GRa-A is a main isoform in mature DCs, and this characteristic expression explains maturation-specific alteration of glucocorticoid sensitivity in these cells (38). GRa-A is highly expressed in brains of toddlers to teenagers, whereas peak expression of GRa-D is observed in those of neonates (39). Thus, these N-terminal human GRa isoforms may differentially transduce glucocorticoid hormone signals to tissues, depending on their selective expression and inherent activities.

The human GR gene has eleven different promoters with their alternative first exons (1A1, 1A2, 1A3, 1B, 1C, 1D, 1E, 1F, 1H, 1I and 1J) (40,41) (Figure 7). Therefore, the human GR gene can produce eleven different transcripts from different promoters that encode the same GR proteins sharing a common exon 2 containing the translating ATG codon. 1A1, 1A2, 1A3 and 1I are located in the distal promoter region spanning ~32,000-36,000 bps upstream of the translation start site, while 1B, 1C, 1D, 1E, 1F, 1H and 1J position in the proximal promoter region located up to ~5,000 bps upstream of such a site (40). Through differential use of these promoters, expression levels of GR protein isoforms can vary considerably among tissues and disease states (40,42). DNA methylation of the human GR gene promoter area is one of the mechanisms that regulate the activity of specific GR gene promoters. Indeed, childhood trauma, which influences development of the borderline personality disorder by affecting the stress-responsive HPA axis, contributes to the alteration of DNA methylation levels of the human GR gene promoter in the brain (43). Elevated DNA methylation in the human GR gene promoter is also found in the brain hippocampus of the patients with major depression (44). Furthermore, the methylation status of the human GR gene promoter in the peripheral blood is highly altered during the perinatal period. Interestingly, preterm infants demonstrate significantly lower levels of the DNA methylation compared to full-term infants, explaining in part relative glucocorticoid insensitivity observed in preterm babies (45).

In addition to selective use/activation-inactivation of the specific GR gene promoters, alternative untranslated 1^st exon transcripts differentially control stability and translational efficiency of their existing GR mRNA, and contribute to differential tissue expression of the GR proteins (46). By employing many splice/translational GR isoforms expressed from different promoters, human GR appears to form at least 256 different combinations of homo- and hetero-dimers with varying expression levels and transcriptional activities. This marked complexity in the transcription/translation of the human GR gene allows cells/tissues to respond differentially to the circulating concentrations of glucocorticoids depending on the needs of respective tissues (20).

Figure 7.

The human (h) GR (NR3C1) gene has 11 different promoters with specific exon 1 sequences. The hGR (NR3C1) gene has 11 different promoters harboring specific exon 1 sequences. Alternative exon 1s are shown as yellow arrows or arrowheads. The 5’ flanking region of the hGR (NR3C1) gene has proximal and distal promoter regions, which respectively span from ~-37,000 to ~-32,000 and from ~-5,000 to ~0, upstream of the translation initiation site located in the exon 2 (shown as “ATG” and arrowhead), and contain exons 1A1, 1A2, 1A3, and 1I, and 1B, 1C, 1D, 1E, 1F and 1H, respectively. Modified from (40,41).

ACTIONS OF GR

Nucleocytoplasmic Shuttling of GRa

In the absence of ligand, GRa resides primarily in the cytoplasm of cells as part of a large multiprotein complex, which consists of the receptor polypeptide, two molecules of hsp90, and several other proteins (28,47-49) (Figure 8). Following ligand binding, the receptor dissociates from the hsps and translocates into the nucleus. The GRa contains two nuclear translocation signals (NL), NL1 and NL2 (Figure 3): NL1 contains a classic basic-type nuclear localization signal (NLS) structure that overlaps with and extends C-terminally from the DBD of GRa (50). The function of NL1 is dependent on importin a, a protein component of the nuclear translocation system, which is energy-dependent and facilitates the translocation of the activated receptor into the nucleus through the nuclear pore. NL2 spans over almost the entire LBD. In the absence of ligand, binding of hsps with the LBD of GRa masks/inactivates NL1 and NL2, thereby maintaining GRa in the cytoplasm. Inside the nucleus, GRa binds to GREs in the promoter regions of target genes. The interaction of GRa with GREs is dynamic, with the GRa binding to and dissociating from GREs in the order of seconds, while the GRE-bound receptor helps other GRas to bind DNA by increasing chromatin accessibility (the mechanism called “assisted loading”), and ultimately up-regulates their steady state association on glucocorticoid-responsive gene promoters (51,52). The above findings were obtained using the multi-copy GREs artificially inserted into the host cell chromatin, but a recent report confirmed them by examining endogenous GREs using a single molecule imaging technique (53). GRa also modulates transcriptional activity of other transcription factors by physically interacting with them. After modulating the transcription of its responsive genes, GRa dissociates from the ligand and slowly returns to the cytoplasm as a component of the heterocomplexes with hsps (54-56). The ubiquitin-proteasomal pathway degrades ligand-bound GRa in the nucleus, facilitating clearance of the receptor from GREs; thus, this system regulates the transcriptional activity of GRalpha in a negative fashion (57,58).

Figure 8.

Intracellular circulation of GR. Circulation of GR between the cytoplasm and the nucleus, and its transcriptional regulation on the glucocorticoid-responsive genes in the nucleus are shown in the panel. GR translocates into mitochondria or lysosomes as well. GREs: glucocorticoid responsive elements; TFREs: transcription factor responsive elements; HSPs: heat shock proteins; TF: transcription factor. From (59).

Several mechanisms have been postulated for the regulation of GRa nuclear export [27]. The Ca²⁺-binding protein calreticulin plays a role in the nuclear export of GRa, directly binding to the DBD of this receptor (60-62). In contrast, the CRM1/exportin and the classic nuclear export signal (NES)-mediated nuclear export machinery does not appear to be functional directly on GR (50,60,63). Rather, NES-harboring and phospho-serine/threonine-binding protein 14-3-3s can bind the human GR phosphorylated at serine 134, and segregates the nuclear GRa into the cytoplasm (64,65) (see also Section 6. FACTORS THAT MODULATE GR ACTIONS, B. Epigenetic Modulation of GRa, Phosphorylation).

In addition to translocating into the nucleus, GRa was reported to shuttle into mitochondria upon ligand activation and to stimulate mitochondrial gene expression by binding to their own DNA (66) (Figure 8). Exposure of rats to stress or corticosterone induces translocation of GRa to mitochondria and modulates mitochondrial mRNA expression (67), indicating that this activity of GRa is evident at an animal level. GRa was also shown to move into the lysosome, which leads to the negative regulation of its transcriptional activity (68).

Mechanisms of GRa-mediated Activation of Transcription

Classically, GRa exerts its transcriptional activity on glucocorticoid-responsive genes by binding to GREs located in the promoter region of these genes (69). The optimal tandem GREs is an inverted hexameric palindrome separated by 3 base pairs, PuGNACANNNTGTNCPy, on which each GRa molecule binds one of the palindromes, forming a homodimer on this binding site through multiple contacts between the 2 receptors (70,71). Recent research indicated that sequence variation of GREs, including 3 non-specific spacer nucleotides, influences the 3-dimensional structure of DBD and modulates the transcriptional activity of whole GRa molecule (72,73); Binding of GRa DBD to GRE DNA sequence induces conformational changes in the dimerization surface located in D-loop through the lever arm, which positions itself between the first a-helix and D-loop (Figure 4A). Two receptors bound on each GRE half site then communicate with each other with their GRE sequence-specific dimerization surfaces, and ultimately develop net transcriptional activity. These findings suggest that DNA GRE is a sequence-specific allosteric modulator of GRa transcriptional activity through alteration of its protein conformation, explaining in part gene-specific transcriptional effects of this receptor.

The GRE-bound GRa stimulates the transcription rates of glucocorticoid-responsive genes by facilitating formation of the transcription initiation complex on the GREs-containing promoter of these genes via its AF-1 and AF-2 transactivation domains (74) (Figure 3). Actions of AF-1 located in NTD of GRa is ligand-independent, while AF-2 is created on GRa LBD upon ligand-binding (75).

The transcription initiation complex attracted and formed on DNA-bound GRa is a mega protein structure that include over 100 proteins with different activities, such as RNA polymerase II and its ancillary factors, general transcription factors and numerous co-regulatory molecules with/without enzymatic activities (74). Research studies aimed to identify molecules interacting with GRa AF-2 have led to several proteins and protein complexes, called coactivators or cofactors, that form a bridge between DNA-bound GRa and the transcription initiation complex, and assist enzymatically with the transmission of the glucocorticoid signal to RNA synthesis promoted by the RNA polymerase II (76) (Figure 9). These include: (1) p300 and the homologous cAMP-responsive element-binding protein (CREB)-binding protein (CBP), which also serve as macromolecular docking “platforms” for transcription factors from several signal transduction cascades, including NRs, CREB, activator protein-1 (AP-1), NF-kB, p53, Ras-dependent growth factor, and signal transducers and stimulators of transcription (STATs) (77). Because of their central position in many signal transduction cascades, the p300/CBP coactivators are also called co-integrators; (2) p300/CBP-associated factor (p/CAF), originally reported as a human homologue of yeast Gcn5, which interacts with p300/CBP and is also a broad transcription coactivator (78,79); and (3) the p160 family of coactivators, which preferentially interact with SRs (80). These include the steroid receptor coactivator-1 (SRC-1), SRC-2, which consists of transcription intermediate factor-II (TIF-II) and the glucocorticoid receptor-interacting protein-1 (GRIP1), and SRC-3, which consists of the p300/CBP/co-integrator-associated protein (p/CIP), activator of thyroid receptor (ACTR) and the receptor-associated coactivator-3 (RAC3) (76,80,81). These 3 subclasses of p160 family coactivators are also called, respectively, as nuclear receptor coactivators (NCoA) 1, 2 and 3.

Figure 9.

Schematic model demonstrating the interaction and activity of HAT coactivators and other chromatin modulators, which are attracted by GR to the promoter region of glucocorticoid-responsive genes. Promoter-associated GR is cleared by the ubiquitin-proteasomal pathway, which regulates turnover of GR on DNA. Modified from (82). AF-1 and -2: activation function-1 and -2; CBP: cAMP-responsive element-binding protein (CREB)-binding protein; DRIP: vitamin D receptor-interacting protein; GREs: glucocorticoid response elements; p/CAF: p300/CBP-associated factor; SWI/SNF: mating-type switching/sucrose non-fermenting; TRAP: thyroid hormone receptor-associated protein.

The p160 coactivators are the first to be attracted to the DNA-bound NRs and help accumulating p300/CBP and p/CAF proteins to the promoter region, indicating that p160 proteins play a pivotal role in NR-mediated transactivation. A study using the cryoelectron microscopy demonstrated detailed attraction modes of p160 proteins and p300/CBP to DNA-bound and ligand-activated ERa (83); Each of the tandem ER response elements (EREs)-bound receptors independently attracts one p160 molecule via the transactivation surface of the receptor created by their AF-1 and AF-2. Then, the two NCoAs attracted to the receptors recruits one p300/CBP molecule to the DNA/receptors/p160s complex through multiple contacts mediated by different portions of the p160 proteins.

In addition to physical interaction and subsequent formation of the transcriptional initiating complex on the DNA-bound receptors by these coactivators (that is assembly of transcriptional initiation complex), these molecules have intrinsic histone acetyltransferase (HAT) activity through which they acetylate specific lysine residues of chromatin-bound histones, loosen the tightly assembled chromatin structure and facilitate access of other transcription factors and transcriptional complexes to the promoter region (76). These HAT coactivators also acetylate specific lysine residues of their own molecules, NRs and other transcription factors, and modulate their mutual protein-protein interaction and/or association to attracted promoters (84-86). The p160 family coactivators and p300/CBP protein contain one or more copies of the coactivator signature motif sequence LxxLL, where L is leucine and x is any amino acid (80,87). LxxLL forms a helical structure, and develops multiple hydrophobic bonds with its leucine residues to the AF-2 surface, which is created by helixes 3, 4 and 12 of the GRa LBD upon binding to ligand glucocorticoid (Figure 10A). p160-type coactivators contain 3 LxxLL motifs in its nuclear receptor-binding box (NRB) located in their central portion (76) (Figure 10B). Each of these motifs demonstrates different affinity to various NRs, indicating that specific p160 proteins participate in the transcriptional activity of particular NRs through preferential use of LxxLL motifs (88). For example, GRa preferentially interacts with GRIP1 p160 protein through C-terminally located 3^rd LxxLL motif of this coactivator (89).

Figure 10.

p160 coactivators physically interact with its multiple LxxLL motifs to the AF-2 surface of GR. A: 3-dimensional interaction image of GR AF-2 and the LXXLL peptide. The GR AF-2 surface has three large pockets into which core leucines (L745, L748 and L749) of the LXXLL peptide deeply bury themselves. There are additional intermolecular contacts that are important for peptide binding, including the electrostatic bonds created between (i) R746 (LXXLL peptide) and D590 (receptor), (ii) D750 (LXXLL peptide) and R585 (receptor) and (iii) D752 (LXXLL peptide) and K579 (receptor). From (89). B: p160-type coactivators (NCoAs) have 3 LxxLL motifs in their NR-binding box (NRB). Linearlized GRIP1 (NCoA2) molecule with NRB located in the middle portion is shown as a representative of the p160-type coactivators (NCoAs). In addition to NRB, GRIP1 has the basic helix-loop-helix (bLHL) and the PAS domains in its N-terminal portion, and p300/CBP-binding domain and one transactivation domain containing the HAT domain in the C-terminus.

The AF-2 transactivation domain of GRa also attracts several other distinct chromatin modulators, such as the mating-type switching/sucrose non-fermenting (SWI/SNF) complex and components of the vitamin D receptor-interacting protein/thyroid hormone receptor-associated protein (DRIP/TRAP) complex (76). The SWI/SNF complex is an ATP-dependent chromatin remodeling factor with a multi-subunit structure in which the ATPase domain functions as the catalytic center (90). Depending on the energy of ATP hydrolysis, the SWI/SNF complex introduces superhelical torsion into DNA. One of its components, SNF2 binds to AF-2 of GRa directly, functioning as an interface between the GRa and the SWI/SNF complex (91). The DRIP/TRAP complex is also a multiprotein conglomerate, which consists of over 10 different proteins, including DRIP205/TRAP220/PBP and components of SMCC (76). The DRIP/TRAP complex may modulate transcription through interaction and modification of general transcription factors, such as TFIIH or the C-terminal tail of the RNA polymerase II. DRIP205/TRAP220 contains two LxxLL motifs through which it binds to the ligand-activated AF-2 directly (92). Since the DRIP/TRAP complex and p160 coactivators use the same motif for interaction with NRs, they may bind to the same site of these receptors and sequentially interact with them for full activation of transcription. Alternatively, they may interact with a particular set of NRs, or have a different effect on different tissues (76,81).

In contrast to the mechanisms of transactivation by AF-2, those of AF-1 are not as well elucidated yet. Using the yeast system, the Ada complex may act on AF-1-mediated transcriptional activation through direct interaction to this module (93). The SWI/SNF complex, TBP and the HAT coactivators, such as p160 and p300/CBP, also physically interact with AF-1 and mediate its transcriptional activity (94-97). In addition, DRIP150, a component of the DRIP/TRAP complex, and the tumor susceptibility gene 101 (TSG101) interact with the AF-1 of the GRa in a yeast two-hybrid screening (98). The RNA coactivator, steroid RNA activator (SRA), also interacts with AF-1 (99). Given that any of these molecules and complexes interact with both AF-1 and AF-2, it is likely that concurrent activation of AF-1 and AF-2 by their common and/or distinct binding partners may be necessary for optimal activation of GRa-mediated transcriptional activity (100).

Several coactivators supporting the particular actions of glucocorticoids have been identified for GRa. The PPARg coactivator-1a (PGC1a) is a ~800 amino acid single polypeptide molecule originally identified as a cofactor physically interacting with PPARg in the yeast two-hybrid screening using a brown adipocyte cDNA library (101). PGC1a has an essential role in thermogeneration and energy metabolism by controlling mitochondrial biogenesis (101). It also regulates gluconeogenesis and cholesterol metabolism, as well as blood pressure and muscle fiber determination through physical interaction with various NRs, transcriptional factors and coactivators, such as PPARa, hepatocyte nuclear factor 4, CREB, nuclear respiratory factors, and p160 and p300/CBP coactivators (101). GRa also interacts physically with PGC1a through the latter’s LxxLL motif and this interaction is important for stimulation of gluconeogenesis through transcriptional stimulation of the 2 key genes respectively encoding the glucose-6-phosphatase (G6P) and the phosphoenolpyruvate carboxykinase (PEPCK) (101). It is known that longevity-associated histone deacetylase Sirt1 regulates PGC1a activity through its deacetylase activity-dependent or -independent manner (102,103). Sirt1 is shown to interact physically with GRa as well, and PGC1a and Sirt1 cooperatively enhance GR-induced transcriptional activity of glucocorticoid-responsive genes (104).

The CREB-regulated transcription coactivator 2 (CRTC2) is a coactivator previously known to be specific to CREB, and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting (105). This coactivator functions also as a coactivator of GRa by physically interacting with its LBD outside of AF-2, and is required for glucocorticoid-mediated early phase gluconeogenesis by supporting the transcriptional activity of GRa on the G6P and PEPCK genes, while PGC1a cooperates with GRa for maintaining a late phase of fasting-induced gluconeogenesis (106).

Presence of numerous transcriptional cofactors that interact with GRa and influence its transcriptional activity indicate that they may have functional redundancy and/or activities specific to each of them, regulating particular sets of GRa-responsive genes. A study employing knockdown of GRalpha cofactors, such as CCAR1, CCAR2, CALCOCO1 or ZNF282, has addressed this important issue: it revealed that knockdown of any of these cofactor molecules resulted in specific impact on the expression of a particular set of glucocorticoid-responsive genes (107), suggesting that each cofactor molecule has distinct transcriptional regulatory activity on GRa, thus their expression profiles in tissues/organs potentially influence the transcriptional activity of GRa in respective tissues.

Emerging Concept on GRa-mediated Transcriptional Repression

GRa has long been believed to exert its transcriptional activity by binding to the classic GREs, which consists of inverted hexameric palindrome separated by 3 base pairs. However, Surjit, et al. identified unique DNA sequences also targeted by the GRa DBD, called “negative” GREs (nGREs), which play substantial roles in gene transrepression caused by GRa (108). The consensus sequence of nGREs is an inverted quadrimeric palindrome separated by 0-2 nucleotide pairs (CTCC(N)0–2GGAGA). In the structural study employing the prototype nGREs found in the thymic stromal lymphoprotein (TSLP) promoter as a model, 2 GRa molecules bound each palindrome as a monomer with different affinity in a head-to-tail fashion, in contrast to GRa-classic GREs where 2 receptors bind DNA in a head-to-head fashion (109) (Figure 11). nGREs are ubiquitously present in the genes repressed by glucocorticoids throughout several animal species, facilitating access of the silencing mediator for retinoid and thyroid hormone receptors (SMRT)/nuclear receptor corepressor (NCoR)-repressing complexes on the agonist-associated GRa bound on these sequences. This is a new concept, indicating that direct binding of GRa through its DBD to DNA sequences distinct from those of the classic GREs mediates glucocorticoid-induced transcriptional repression. However, a genome-wide study revealed that classic GREs and the “new” nGREs both contribute to transactivation and transrepression of glucocorticoid-responsive genes, suggesting that GRa-targeting DNA sequences per se are insufficient to confer direction of transcriptional regulation, but epigenetic factors and subsequent chromatin modification may play critical roles (110).

Figure 11.

GR binds nGREs as a monomer. GR binds nGREs as a monomer at each of its half site (A) in contrast to its binding as a homo-dimer to classic GREs (B). nGREs of the mouse TSLP gene is used as an example. Images are from the PDB Website (www.rcsb.org). Image data for GR interaction with nGREs and classic GREs are DOI: 10.2210/pdb4hn5/pdb and DOI: 10.2210/pdb3g9m/pdb, respectively.

Interaction of GRa with Transcription Factors

Glucocorticoids exert their diverse effects through its single receptor protein module, the GRa. In addition to direct regulation of gene expression through GRa/DNA interaction, these hormones affect other signal transduction cascades through mutual protein-protein interactions between specific transcription factors and GRa, influencing the former’s ability to stimulate or inhibit the transcription rates of the respective target genes.

The protein-protein interaction of GRa with other transcription factors may take place on the promoters that do not contain GREs (tethering mechanism), as well as on those having both GRE(s) and responsive element(s) of the transcription factors that interact with GRa (“composite promoters”) (111) (Figure 12). Repression of the transactivation activity of other transcription factors through protein-protein interaction may be particularly important in suppression of immune function and inflammation by glucocorticoids (112,113). Substantial part of the effects of glucocorticoids on the immune system may be explained by the interaction between GRa and NF-kB, AP-1 and probably STATs (114-116). It was also reported that GRa directly interacts with the transcription factors “T-box expressed in T-cells” (T-bet) and GATA-3, which play key roles respectively in the differentiation of T helper-1 and T helper-2 lymphocytes (117,118). GRa also influences indirectly the actions of the interferon regulatory factor-3 (IRF-3) through the p160 nuclear receptor GRIP1, by competing with this factor for binding to the coactivator (119). These transcription factors are important for the regulation of immune function and the above interactions may explain some GR actions on the immune system. The following subsections will discuss GRa-interacting transcription factors and their effects on GRa-induced transcriptional activity.

Figure 12.

Three different modes of transcriptional regulation of the glucocorticoid-responsive promoters by GR. GR may interact with other transcription factors directly or indirectly. Protein(s) or protein complex(es) may intermediate their interaction in the latter case. GREs: glucocorticoid responsive elements; TF: transcription factor; TFREs: transcription factor responsive elements

GENOME-WIDE TRANSCRIPTIONAL REGULATION BY GRa

Chromatin-based Regulation of GRa Transcriptional Activity

GRa regulates expression of glucocorticoid-responsive genes by influencing their transcriptional activity through direct or indirect interaction with their enhancer/promoter regions. In eukaryotic cells, DNA is packed into chromatin by associating with numerous nuclear proteins, such as histones and chromatin-modifying factors (175,176). Double-stranded DNA wraps by 1.67 turns around a histone octamer that consists of 2 copies of each core histones H2A, H2B, H3 and H4, and forms the smallest structural unit called “nucleosome”, which is further compacted into a higher order chromatin. Nucleosome-associated histones possess a highly flexible N-terminal tail whose chemical modifications, such as acetylation and methylation at specific lysine (K) residues, modulate accessibility of GRa to its target DNA sequences residing in chromatin. Chromatin is further packed into the 3-dimensional structure called topologically associated domains (TADs) in which several protein-coding gene bodies, promoters and regulatory elements interact with each other through formation of chromatin looping, and their modes of interaction alter in different cellular circumstances. A poly-ZNF protein CTCF plays a central role in the formation of chromatin looping by cooperating with the cohesion protein complex and other accessory factors, including the transcription factor IIIC (TFIIIC), ZNF143, PR domain zinc finger protein 5 (PRDM5) and chromodomain helicase DNA-binding protein 8 (CHD8) (147,149) (Figure 13). In addition to CTCF, interaction of transcription factors, such as between GRa and NF-kB, influences formation of chromatin looping possibly through cooperation with CTCF (177). A study using a new technique called Hi-C (high throughput 3C) further revealed that even chromosomes are packed into the nucleus with some orders shared by many tissues/organs (178,179).

Figure 13.

Organization of the topologically associated domain (TADs) and chromatin looping promoted by CTCF for differential expression of glucocorticoid-responsive genes. CTCF organizes 3-dimensional chromatin interaction for the formation of TADs and chromatin looping, in cooperating with the cohesion protein complex and other component proteins. Chromatin loop-forming activity of CTCF is essential for differential use of enhancers/promoters by GR-responding genes, and underlies organ/tissue-specific actions of glucocorticoids. Modified from (147).

In rat liver, more than 11,000 GR-binding sites (GBSs) are identified primarily at intergenic distal and intronic regions, but only ~10% of GBSs are located in the promoter area (~2.5 kbs from the transcription start site: TSS), consistent with the fact that distantly located enhancer regions can communicate with the gene promoter through gene looping (180,181). Interestingly, ~80-90% of GRa-accessible sites exists prior to glucocorticoid addition/GRa stimulation, while their distribution is highly tissue-specific, indicating that local tissue factor(s) mainly determine(s) the sets of genes responsive to glucocorticoids by regulating chromatin accessibility (180). Indeed, some transcription factors, such as C/EBPb, AP-1 and FoxA1, have their binding sites close to GBSs (thus, composite sites) and act as tissue-specific priming factors (or pioneer factors) for the access of GRa to GBSs, respectively in murine mammary epithelial cells, rat liver and human prostate cancer cells (181-183). These pre-existing GBSs are enriched with CpG islands and are generally demethylated, further suggesting that DNA methylation also contributes negatively to the opening of GBSs (184). However, a study revealed that GRa can act as a pioneer factor for several other transcription factors previously reported to be pioneer factors for GRa (185). This report indicates that GRa can function both as a pioneer and a dependent factor based on the composition of the binding sites in the regulatory elements and/or local chromatin conditions.

FACTORS THAT MODULATE GR ACTIONS

EPIGENETIC MODULATION OF GRa

Acetylation and CLOCK-mediated Counter Regulation of Target Tissue Glucocorticoid Action against Diurnally Fluctuating Circulating Glucocorticoids

All SRs including GRa are acetylated by several acetyltransferases, such as p300, p/CAF and Tip60, and have common acetylation sites in a consensus amino acid motif, KXKK, located in their hinge region (240-242). The human GRa is acetylated at lysine 494 and 495 within an acetylation motif also located in its hinge region, and was reported to be deacetylated by the HDAC2, an effect that is required for suppression of NF-kB-induced transcriptional activity by the activated GRa (243) (Figure 14). This finding indicates that acetylation of the GRa at these lysine residues attenuates the repressive effect of GRa on this transcription factor. In agreement with these results, we recently found that the Clock transcription factor acetylates GRa at the multiple lysine cluster that includes lysines 494 and 495, and represses GRa-induced transcription of several glucocorticoid-responsive genes (244). Clock, the “circadian locomotor output cycle kaput”, and its heterodimer partner “brain-muscle-arnt-like protein 1” (Bmal1), belong to the basic helix-loop-helix (bHLH)-PER-ARNT-SIM (PAS) superfamily of transcription factors, and play an essential role in the formation of the diurnal oscillation rhythms of the circadian CLOCK system (245). The CLOCK system, located in the suprachiasmatic nucleus (SCN) of the brain hypothalamus, acts as the “master” oscillator and generator of the body’s circadian rhythm, while the peripheral CLOCK system, virtually distributed in all organs and tissues including the CNS outside the SCN, acts generally as a “slave” CLOCK under the influence of the central SCN CLOCK. The Clock transcription factor shares high amino acid and structural similarity with the activator of thyroid receptor (ACTR), a member of the p160-type nuclear receptor coactivator family with inherent histone acetyltransferase activity, and thus, has such an enzymatic function (246).

Figure 14.

Distribution of the amino acid residues of the human GR susceptible to acetylation, phosphorylation, ubiquitination or SUMOylation. Human GR has 4 acetylation sites (lysines: K at amino acid position 480, 492, 494 and 495, shown with “A”), at least 5 phosphorylation sites (serines: S at amino acid position 45, 203, 211, 226 and 395, shown with “P”), 1 ubiqitination site (Lysine: K at amino acid position 419, shown with “U”) and 3 SUMOylation sites (Lysines: K at amino acid position 277, 293 and 703, shown with “S”).

Clock physically interacts with GRa LBD through its nuclear receptor-interacting domain (NRID) in its middle portion, and acetylates human GRa at amino acids 480, 492, 494 and 495. Acetylation of GRa attenuates binding of the receptor to GREs, and hence, represses GR-induced transactivation of the GRE-driven promoters (244) (Figure 15). Since the lysine residues acetylated by Clock are located in the C-terminal extension (CTE) that follows DBD and plays a role in DNA recognition by SRs (247), it is likely that acetylation of these residues reduces binding of GRa to GREs by altering the action of CTE. The part of the hinge region acetylated by Clock also overlaps with the nuclear localization signal (NL)-1 (50,244), thus it is also possible that acetylation of GRa alters nuclear translocation of this receptor. It is well known that the central master CLOCK located in SCN creates diurnal fluctuation of circulating cortisol, therefore peripheral CLOCK-mediated repression of GRa transcriptional activity in glucocorticoid target tissues functions as a local counter regulatory mechanism for oscillating circulating cortisol (248).

Figure 15.

Clock/Bmal1 suppresses GR-induced transcriptional activity through acetylation. Clock physically interacts with GR LBD through its nuclear receptor-interacting domain and suppresses GR-induced transcriptional activity by acetylating with its intrinsic HAT activity a lysine cluster located in the hinge region of the GR (A) through which Clock reduces affinity of GR to its cognate DNA GREs (B). A: acetylation; Bmal1: brain-muscle-arnt-like protein 1; DBD: DNA-binding domain; GREs: glucocorticoid response elements; HR: hinge region; K: lysine residue; LBD: ligand-binding domain; NTD: N-terminal domain. From (244).

In addition to the above findings obtained in in vitro cellular systems, we examined the acetylation status of human GRa and the expression of Clock-related and glucocorticoid-responsive genes in vivo and ex vivo, using peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers (249). The levels of acetylated GRa were higher in the morning and lower in the evening, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone, however, some of these genes did not show the expected diurnal mRNA fluctuations in vivo. Instead, their mRNA oscillated in a Clock- and a GRa acetylation-dependent fashion in the absence of endogenous glucocorticoid ex vivo, indicating that circulating cortisol might prevent circadian GRa acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. These findings indicate that peripheral CLOCK-mediated circadian acetylation of GRa functions as a target tissue- and gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night (36). Indeed, in another study where we measured mRNA expression of ~190 GRa action-regulating and glucocorticoid-responsive genes in subcutaneous fat biopsies from 25 obese subjects, we found that the levels of evening cortisol were much more important than those in the morning to regulate mRNA expression of glucocorticoid-responsive genes in this human tissue (250). It appears that higher sensitivity of tissues to circulating glucocorticoids in the evening due to reduced GRa acetylation by CLOCK underlies stronger impact of evening serum cortisol levels to glucocorticoid-regulated gene expression compared to morning levels.

The circadian CLOCK system and the HPA axis regulate each other’s activity through multilevel interactions in order to ultimately coordinate homeostasis against the day/night change and various unforeseen random internal and external stressors (251,252). For example, one CLOCK transcription factor Cry2 interacts with GRa and represses its transcriptional activity (253). Furthermore, GRa binds GREs located in the promoter region of the Per1, Per2 and other CLOCK components and stimulate their expression, an effect that contributes to resetting of the circadian rhythms by glucocorticoids (254,255). The peripheral CLOCK system residing in the adrenal glands contributes to the creation of circadian glucocorticoid secretion from this organ in addition to diurnally secreted ACTH from the pituitary gland (256). An important study further revealed new local factors, which also regulate circadian production of glucocorticoids in the adrenal glands: the intermediate opioid peptides secreted from the adrenal cortex influence in a paracrine fashion the amplitude of the serum corticosterone oscillations in mice through the C-X-C motif chemokine receptor 7 (CXCR7), a b-arrestin-biased G-protein-coupled receptor expressed on the adrenocortical cells (257).

Based on the above-indicated multilevel interaction between the CLOCK system and the HPA axis, uncoupling of or dysfunction in either system alters internal homeostasis and causes pathologic changes virtually in all organs and tissues, including those responsible for intermediary metabolism and immunity (248,251,252). Disrupted coupling of cortisol secretion and target tissue sensitivity to glucocorticoids may account for (1) development of central obesity and the metabolic syndrome in chronically stressed individuals, whose HPA axis circadian rhythm is characterized by blunting of the evening decreases of circulating glucocorticoids, as a result of enhanced input of higher centers upon the hypothalamic PVN’s secretion of CRH and arginine vasopressin (AVP); and (2) increased cardiometabolic risk and increased mortality of night-shift workers or subjects exposed to frequent jet-lag because of traveling across time zones (248,258). In addition, given that tissue sensitivity to glucocorticoids is increased in the evening as mentioned above (thus, evening cortisol levels have stronger impact to gene expression than those in the morning), supplemental administration of high-dose glucocorticoids at night for the treatment of adrenal insufficiency or congenital adrenal hyperplasia may increase a possibility of glucocorticoid-related side effects. Furthermore, administration of glucocorticoids at a specific period of the circadian cycle might increase their pharmacological efficacy, while at the same time reducing their unwanted side effects, because CLOCK differentially regulates transactivational and transrepressive actions of glucocorticoids, which are respectively correlated with side-effects and beneficial anti-inflammatory activities of these compounds used at pharmacological concentrations (258).

NON-CODING RNAS

Human genome expresses numerous non-protein-coding RNAs in addition to protein-coding mRNAs. Indeed, over half of the genome sequence expresses RNAs in both directions either as single- or double-stranded RNAs (320,321). Classic examples of the former RNAs are ribosomal RNAs and transfer RNAs, while several distinct new members have been identified recently (322). Depending on their size, non-coding (nc) RNAs are empirically categorized as short (~200 bs) or long (>200 bs) ncRNAs. The former family includes micro (mi) RNAs, small interfering (si) RNAs, small nucleolar (sno) RNAs, piwi (pi) RNAs and transcription start site (TSS)-associated RNAs, while the latter consists of long intergenic (linc) RNAs, enhancer-associated (e) RNAs, exon-encoding long ncRNAs, circular (c) RNAs, promoter-associated RNAs and others. ncRNAs are also produced from protein-encoding mRNAs through nuclease digestion, such as 3’ UTR RNAs (323). Recently, some of these distinct classes of ncRNAs have been revealed to regulate mRNA/protein degradation and transcriptional activity of GRa and other NRs. In this subsection, new findings on miRNAs and long ncRNAs will be discussed.

Long Non-coding (lnc) RNAs

Several lncRNAs regulate the transcriptional activity of GRa and/or other SRs. The steroid RNA coactivator (SRA) is a prototype lncRNA that regulates the transcriptional activity of several SRs (99). SRA was originally cloned in the yeast two-hybrid assay by using NTD of the PR as bait. It enhances ligand-induced transcriptional activity of AR, ER, GRa and PR. It is found in the complex containing the p160 coactivator SRC1, and regulates transcriptional activity in part by associating with the SRA stem-loop-interacting RNA binding-protein (SLIRP) and the RISC complex (99,338,339). Recently, SRA was shown to function also as a repressor of transcription, acting as a scaffold for a repressor complex (340).

The growth arrest-specific 5 (Gas5), which is a multi-exon-containing ncRNA with a poly-A tail, is accumulated in cells whose growth is arrested due to lack of nutrients or growth factors (341). Gas5 functions as a repressor of the GRa and some other SRs (342). Gas5 sensitizes cells to apoptosis by suppressing glucocorticoid-mediated induction of several responsive genes, including those encoding the cellular inhibitor of apoptosis 2 and the serum/glucocorticoid-responsive kinase. Gas5 binds GRa DBD and acts as a decoy “GRE”, thus, it competes with DNA GREs for binding to GRa (Figure 16). These findings indicate that Gas5 is a ribo-repressor of the GRa, influencing cell survival and metabolic activities during starvation by modulating the transcriptional activity of GRa. Accumulation of Gas5 upon growth arrest or starvation was previously demonstrated in a cellular context, but a study revealed that fasting of mice also accumulates Gas5 in their metabolic organs, such as liver and adipose tissues, through modulation of the mammalian target of rapamycin (mTOR) signaling pathway, but not in the brain and immune organs including thymus and spleen (343). Since basal expression levels of Gas5 in the immune organs are much higher than those of the metabolic organs, Gas5 may have a regulatory activity on GRa in the immune system independent to the nutrient/energy availability, as evidenced by the fact that Gas5 is differentially expressed in blood leukocytes of the patients with autoimmune, inflammatory or infectious diseases (343). Moreover, Gas5 has been shown to be implicated in glucocorticoid response in children with inflammatory bowel disease (344), in multiple sclerosis (345-347), in human beta cell dysfunction (348), as well as in hematologic malignancies (349,350). Similar to Gas5, PRNCR1 (also known as PCAT8) and PCGEM1 bind AR DBD and enhance the transcriptional activity of this receptor (351). These lncRNAs are highly expressed in the prostate gland, and play a role in the androgen-dependent development of prostate cancer. Their effects on GRa have not been tested as yet.

Figure 16.

Interaction model of the Gas5 RNA “GRE” to GR DBD and the molecular actions of Gas5 on GR-induced transcriptional activity. A: 3-Dimenstional structure of Gas5 “GRE”-mimic and its interaction model with GR DBD. From (342). B: Schematic model of Gas5 molecular actions on GR-induced transcriptional activity. Gas5 accumulated in response to growth arrest/starvation binds GR DBD and attenuates GR-induced transcriptional activity by competing with DNA GREs located in the promoter region of glucocorticoid-responsive genes.

THE SPLICING VARIANT GRbeta ISOFORM

The GRb isoform, which is expressed from the human GR gene through alternative use of its specific exon 9b, is known to have a dominant negative activity on classic GRa-induced transcriptional activity (21,352). This isoform was originally identified in humans, and was also reported in zebrafish, mice and rats (19,353-355). Since human (h) GRb shares the first 727 amino acids from the N-terminus with hGRa (19,356) (Figure 3), hGRb shares the same NTD and DBD with hGRa, but has a unique “LBD”. The divergence point (amino acid 727) of hGRa and hGRb is located at the C-terminal end of helix 10 in the hGRa LBD, therefore the hGRb “LBD” does not have helices 11 and 12 of the hGRa. As these helices are important for forming the ligand-binding pocket and for the creation of the AF-2 surface upon ligand binding (31), GRb cannot form an active ligand-binding pocket, does not bind glucocorticoids, and so, does not directly regulate GRE-containing, glucocorticoid-responsive gene promoters. In the absence of the hGRb “LBD”, the truncated hGR consisting of the NTD and DBD is transcriptionally active on GRE-containing promoters (357), thus the hGRb “LBD” somehow attenuates the transcriptional activity of the other subdomains of the molecule on GRE-driven promoters.

The dominant negative activity of GRb was first demonstrated in transient transfection-based reporter assays using GRE-driven reporter genes (21,358), but was subsequently confirmed on endogenous, glucocorticoid-responsive genes, such as the mitogen-activated protein kinase phosphatase-1 (MPK-1), myocilin and fibronectin (359,360). Further, GRb was shown to attenuate glucocorticoid-induced repression of the TNFa and interleukin (IL)-6 genes (359). We also confirmed this negative effect of GRb on GRa-mediated transrepression using microarray analyses (361). Several mechanisms explaining this GRb function have been reported, including (1) competition for GRE binding through their shared DBD, (2) heterodimerization with GRa and (3) coactivator squelching through the preserved AF-1 domain (21,357,358). All these different mechanisms of actions appear to be functional, depending on the promoters and the tissues affected by this GR isoform. Recently, the human GRb was shown to possess intrinsic transcriptional activity independent to its dominant negative effect on GRa-induced transcriptional activity, while the physiologic role(s) of this activity remain(s) to be examined (342,361,362) (see below). Inside the cells, hGRb can localize both in the cytoplasm and in the nucleus (363,364).

Similar to the human GR gene, the zebrafish (z) GR gene consists of 9 exons and produces zGRa and zGRb proteins, which contain 746 and 737 amino acids, respectively (353) (Figure 17). zGRa and zGRb share the N-terminal 697 amino acids, whereas they have specific C-terminal portions, which contain 47 and 40 amino acids, respectively. In contrast to hGRa and hGRb, which are produced through alternative use of specific exon 9a and 9b, zGRa and zGRb are formed as a result of intron retention (353). zGRa and zGRb use exon 1 to exon 8 for their common N-terminal 697 amino acids. zGRa uses exon 9 for its specific C-terminal portion, while zGRb continuously employs the rest of exon 8 and uses a stop codon located at the 3’ portion of this exon to express its specific C-terminal peptide (353). Protein alignment comparison of hGRb and zGRb indicated that these two molecules employ exactly the same divergence point, while their b isoform-specific C-terminal peptides show little sequence homology (353). These pieces of molecular information indicate that hGRb and zGRb evolved independently. Mouse (m), and recently, rat (r) GRb are also shown to produce in the same fashion as zGRb, indicating that intron retention may be a general mechanism for expressing this receptor isoform in organisms, while splicing-mediated expression employed by hGRb is rather unique (355,365). Nevertheless, zebrafish, mouse and rat GRb demonstrated the same functional properties as those of hGRb, namely, inability to bind glucocorticoids, a dominant negative activity on respectively zGRa-, mGRa- and rGRa-induced transactivation of GREs-drive promoters, and a strikingly similar tissue distribution as hGRb (353,365). Thus, hGRb, mGRb, rGRb and zGRb were produced through convergent evolution, most likely developed through a strong requirement of this type of GR isoform in the survival of these species. Indeed, the presence of nonligand-binding C-terminal variants is not unique to the GR. Similar to the human, mouse, rat and zebrafish GR, several other human NRs, e.g. ERb, TRa, vitamin D receptor (VDR), constitutive androstane receptor (CAR), dosage-sensitive sex reversal-1 (DAX-1), NURR-2, NOR-2, PPARα and PPARγ, all have C-terminally truncated receptor isoforms that are defective in binding to cognate ligands and have a dominant negative activity on their corresponding classic receptors (366-375). This suggests that evolution has allowed the development and retention of such alternative NRs, probably because they play important biologic roles.

Figure 17.

Genomic and complementary DNA and protein structure of the zebrafish GR isoforms. The zebrafish (z) GR gene consists of 9 exons. The zGR gene expresses zGRa and zGRb splicing variants through intron retention (353). C-terminal gray colored and shaded domains in zGRa and zGRb show their specific portions. They are respectively encoded by exon 9 and the 3’ portion of exon 8, which are also shown in the same labeling in the genomic and complementary DNA models. Mouse and rat GR are produced with the same mechanism (355). Modified from (352). DBD: DNA-binding domain; LBD: Ligand-binding domain; NTD: N-terminal domain; UTR: untranslated region.

Biological actions of GRb and associated molecular mechanisms have been examined further during the last years. Using adeno-associated virus-based transfer of GRb to mouse liver, this isoform modulates mRNA expression of many genes in this organ including those related to endocrine system disorders, cancer, gastrointestinal diseases and immune diseases/inflammatory response both in a GRa-dependent and -independent fashions (376). Specifically, GRb attenuates GRa-dependent expression of the hepatic PEPCK gene and hepatic gluconeogenesis, while GRb stimulates expression of STAT1 through GREs located in the intergenic area close to the latter gene. The latter finding suggests that GRb can regulate gene expression by binding to classic GREs, in contrast to the previous findings obtained with GRE-driven reporter genes. In addition, GRb antagonizes to GRa-mediated suppression of bladder cancer cell migration and myogenesis of cardiomyocytes (377,378). GRb suppresses PTEN expression and enhances insulin-stimulated growth by stimulating the phosphorylation of AKT1 in a GRa-independent fashion (379). Further, GRb acts as a coactivator of T-cell factor-4 and enhances glioma cell proliferation also in a GRa-independent manner (380).

Several clinically oriented investigations suggest that GRb is responsible for the development of tissue-specific insensitivity to glucocorticoids in various disorders, most of them associated with dysregulation of immune function. They include glucocorticoid-resistant asthma, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis, chronic lymphocytic leukemia and nasal polyps (381-387). In these studies, various immune cells express elevated levels of GRb, which correlate with reduced sensitivity to glucocorticoids. Viral infection also stimulates GRb expression: for example, its expression in the peripheral mononuclear cells is strongly stimulated in the infants with bronchiolitis caused by the respiratory syncytial virus infection, and its expression levels are correlated with severity of the disease (388). Elevated levels of pro-inflammatory cytokines, such as IL-1, -2, -4, -7, -8 and -18, TNFa, and interferons a and g, might be responsible for increased GRb expression in cells from patients with these pathologic conditions, as these cytokines experimentally stimulate the expression of GRb in lymphocytes, neutrophils or airway smooth muscle cells (389-394). Further, presence of a single nucleotide polymorphism in the 3’ UTR of the hGRb mRNA (rs6198G allele), which increases its stability, and thus, causes elevated expression of the GRb protein, was associated with increased incidence of RA, SLE, high blood pressure, ischemic heart disease and nasal carriage of Staphylococcus aureus (382,395-397), possibly through inhibition of glucocorticoid actions by the increased concentrations of GRb. These pieces of clinical evidence further support that GRb has a dominant negative activity on GRa-induced transcription inside the human body, functioning as a negative regulator of glucocorticoid actions in local tissues.

PATHOLOGIC MODULATION OF GR ACTIVITY

Natural Pathologic GR Gene Mutations that Cause Familial/Sporadic Generalized Glucocorticoid Resistance or Chrousos Syndrome

Mutations in the human GR gene result in familial/sporadic generalized glucocorticoid resistance syndrome [see reviews (398-402)]. Since this syndrome was first reported by Chrousos et al. (403), we now call it as “Chrousos syndrome” (398,404). The condition is characterized by hypercortisolism without Cushingoid features (403,405). To overcome reduced sensitivity to glucocorticoids in tissues, affected subjects have compensatory elevations in circulating cortisol and ACTH concentrations, which maintain circadian rhythmicity and appropriate responsiveness to stressors, and resistance of the HPA axis to dexamethasone suppression, but no clinical evidence of hypercortisolism (404). Instead, the excess ACTH secretion causes increased production of adrenal steroids with mineralocorticoid activity, such as deoxycorticosterone (DOC) and corticosterone and/or androgenic activity, such as androstenedione, dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S); The former accounts for symptoms and signs of mineralocorticoid excess, such as hypertension and hypokalemic alkalosis. The latter accounts for the manifestations of androgen excess, such as ambiguous genitalia and precocious puberty in children, acne, hirsutism and infertility in both sexes, male-pattern hair-loss, menstrual irregularities and oligo-anovulation in females, and adrenal rests in the testes and oligospermia in males. The clinical spectrum of the condition is broad and a large number of subjects may be asymptomatic, displaying biochemical alterations only (404).

An increasing number of kindreds and sporadic cases with abnormalities in the GR number, affinity for glucocorticoid, stability, and translocation into the nucleus have been reported (406-414). The molecular defects that have been elucidated are presented in Figure 18 and Table 1. The propositus of the original kindred was a homozygote for a single nonconservative point mutation, replacing aspartic acid with valine at amino acid 641 in the LBD of GRa; this mutation reduces the binding affinity of the affected receptor for dexamethasone by three-fold and causes loss of transactivation activity (411). The proposita of the second family had a 4-base deletion at the 3’-boundary of exon 6, removing a donor splice site. This results in complete ablation of one of the GR alleles in affected members of the family (412). Recent research employing mice with GR haploinsufficiency confirmed that ablation of one GR allele is sufficient to develop generalized glucocorticoid resistance (415). The propositus of the third kindred had a single homozygotic point mutation at amino acid 729 (valine to isoleucine: V729I) in the LBD, which reduced both the affinity and the transactivation activity of GRa (414). Several pathologic heterozygotic or homozygotic mutations of the GR gene have been recently identified in the patients as listed in Table 1 (403,411-444).

Figure 18.

Location of the known human GR mutations causing Chrousos syndrome or its mirror image, sporadic glucocorticoid hypersensitivity, in the human GR (NR3C1) gene (A) and in the linearized hGR protein molecule (B). Nucleoside numbers of the mutated sites are determined by the definition employing adenine of the translation initiation site as number 1.

Table 1.

Mutations in the NR3C1 Gene Causing Familial/Sporadic Generalized Glucocorticoid Resistance (Chrousos) or Hypersensitivity Syndromes

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Authors	cDNA*	Amino acid	Molecular Defects	Genotype	Phenotype
Chrousos et al. (403) Hurley et al. (411)	1922A>T	Asp641Val	Transactivation: Decreased Affinity to ligand: Decreased (x3) Nuclear translocation: 22 min Abnormal interaction with GRIP1	Homozygous	Hypertension Hypokalemic alkalosis
Karl et al. (412)	4bp deletion in exon-intron 6		GRa number: 50% reduction Inactivation of affected allele	Heterozygous	Hirsutism Male-pattern hair-loss Menstrual irregularities
Malchoff et al. (414)	2185G>A	Val729Ile	Transactivation: Decreased Affinity to ligand: Decreased (x4) Nuclear translocation: 120 min Abnormal interaction with GRIP1	Homozygous	Precocious puberty Hyperandrogenism
Karl et al. (413) Kino et al. (416)	1676T>A	Ile559Asn	Transactivation: Decreased Transdominance (+) Decrease in GR binding sites Nuclear translocation: 180< min Abnormal interaction with GRIP1	Heterozygous	Hypertension Oligospermia Infertility
Ruiz et al. (418) Charmandari et al. (419)	1430G>A	Arg477His	Transactivation: Decreased No GREs binding Decrease in GR binding sites Nuclear translocation: 20 min	Heterozygous	Hirsutism Fatigue Hypertension
Ruiz et al. (418) Charmandari et al. (419)	2035G>A	Gly679Ser	Transactivation: Decreased Affinity to ligand: Decreased (x2) Nuclear translocation: 30 min Abnormal interaction with GRIP1	Heterozygous	Hirsutism Fatigue Hypertension
Mendonca et al. (417)	1712T>C	Val571Ala	Transactivation: Decreased Affinity to ligand: Decreased (x6) Nuclear translocation: 25 min Abnormal interaction with GRIP1	Homozygous	Ambiguous genitalia Hypertension Hypokalemia Oligo-amenorrhea
Vottero et al. (420)	2241T>G	Ile747Meth	Transactivation: Decreased Transdominance (+) Affinity to ligand: Decreased (x2) Nuclear translocation: Decreased Abnormal interaction with GRIP1	Heterozygous	Cystic acne Hirsutism Oligo-amenorrhea
Charmandari et al. (421)	2318T>C	Leu773Pro	Transactivation: Decreased Transdominance (+) Affinity to ligand: Decreased (x2.6) Nuclear translocation: 30 min Abnormal interaction with GRIP1	Heterozygous	Fatigue Anxiety Acne Hirsutism Hypertension
Charmandari et al. (431)	2209T>C	Phe737Leu	Transactivation: Decreased Transdominance (+) Affinity to ligand: Decreased (x1.5) Nuclear translocation: 180 min	Heterozygous	Hypertension Hypokalemia
Charmandari et al. (430)	1201G>C	Asp401His	Transactivation: Increased Transdominance (-) Affinity to ligand: no change Nuclear translocation: Normal	Heterozygous	Hypertension Diabetes mellitus Accumulation of visceral fat
McMahon et al. (426)	2bp (TG) deletion at 2318 and 2319	Phe774Serfs⃰	No transactivation activity No ligand-binding activity	Homozygous	Severe hypoglycemia developed 1 day after birth Hypertension Fatigues with feeding
Nader et al. (422) (443)	2141G>A	Arg714Gln	Transactivation: Decreased Transdominance (+) Affinity to ligand: Decreased (x2.0) Nuclear translocation: 20 min Abnormal interaction with GRIP1	Heterozygous Heterozygous	Hypoglycemia developed at age 2 years and 10 months Hypertension Accelerated bone age Mild clitoromegaly Infertility
Bouligand et al. (429)	1405C>T	Arg469Ter	Transactivation: Decreased Affinity to ligand: Decreased Nuclear Translocation: No	Heterozygous	Bilateral adrenal hyperplasia Hypertension Hypokalemia
Zhu et al. Nicolaides et al. (423) (424)	1667C>T	Threo556Ile	Transactivation: Decreased Transdominance: No Affinity to ligand: Decreased Nuclear translocation: 50 min	Heterozygous	Bilateral adrenal hyperplasia
Roberts et al. (428)	1268T>C	Val423Ala	Transactivation: Decreased Transdominance: No Affinity to ligand: no change Nuclear translocation: 2.6-fold delay	Heterozygous	Hypertension
Nicolaides et al. (425)	2177A>G	His726Arg	Transactivation: Decreased Transdominance: No Affinity to ligand: Decreased Nuclear translocation: 60 min	Heterozygous	Hirsutism Acne Alopecia Fatigue Anxiety Irregular menstrual cycle
Lin et al. (432)	26C>G	Pro9Arg	Not performed	Heterozygous	Hypertension
Paragliola et al. (433)	367G˃T	Glu123Ter	Not performed	Heterozygous	Chronic fatigue Anxiety Hirsutism Irregular menstrual cycles Infertility
Tatsi et al. (434)	592G˃T	Glu198Ter	Not performed	Compound heterozygous	Hypertensive encephalopathy
Al Argan et al. (435)	1392delC	Ile464Ilefs⃰	Not performed	Heterozygous	Low body weight Hyperandrogenism Severe anxiety Adrenocortical hyperplasia
Vitellius et al. (436)	1429C˃A	Arg477Ser	Cytoplasm to nuclear translocation: Decreased DNA binding: (-) Dominant negative effect: (-) Transactivation: (-)	Heterozygous	Obesity
Velayos et al. (437)	1429C˃T	Arg477Cys	Not performed	Heterozygous	Mild hirsutism
Vitellius et al. (436)	1433A˃G	Tyr478Cys	Cytoplasm to nuclear translocation: Decreased DNA binding: Weak and delayed Dominant negative effect: (-) Transactivation: Decreased	Heterozygous	Adrenal mass
Vitellius et al. (438)	1471C˃T	Arg491Ter	Transactivation: (-)	Heterozygous	Bilateral adrenal hyperplasia
Vitellius et al. (438)	1503G˃T	Gln501His	Transactivation: Decreased	Heterozygous	Bilateral adrenal hyperplasia
Ma et al. (439)	1652C˃A	Ser551Tyr	Ligand binding: Decreased Cytoplasm to nuclear translocation: Decreased Transactivation: Decreased	Homozygous	Fatigue Hypokalemia Hypertension Polyuria
Velayos et al. (437)	1762_1763insTTAC	His588Leufs⃰	Not performed	Heterozygous	Hirsutism Chronic fatigue Anxiety
Cannavò et al. (440)	1915C˃G	Leu595Val	Not performed	Not available	Hirsutism Amenorrhea Hypertension
Trebble et al. (441)	1835delC	Ser612Tyrfs⃰	Protein expression: (-) Ligand binding: (-) Cytoplasm to nuclear translocation: (-) Dominant negative effect: Yes Transactivation: (-)	Heterozygous	Fatigue
Vitellius et al. (442)	1980T˃G	Tyr660Ter	Transactivation: (-)	Heterozygous	Hypertension
Vitellius et al. (436)	2015T˃C	Leu672Pro	Protein expression: Decreased Ligand binding: (-) Cytoplasm to nuclear translocation: (-) DNA binding: (-) Dominant negative effect: No Transactivation: (-)	Heterozygous	Adrenal mass
Donner et al. (444)	2317_2318delCT	Leu773Valfs⃰	Protein expression: slightly reduced Transactivation: Decreased Dominant negative effect: No Ligand binding: (-)	Heterozygous	Hypertension

We examined the impact of 10 pathologic GRa point mutations (559N, V571A, V575G, D641V, G679S, R714Q, V729I, F737L, I747M and L773P) to the molecular structure of the GRa LBD focusing on its ligand-binding pocket and AF-2 surface by using computer-based molecular simulation, and found some rules on the molecular disruption of these structural units by the mutations (89); (1) Topology of the peptide backbones is highly preserved in pathologic GRa mutant LBDs (Figure 19A). This result suggests that alteration in property and/or positioning of the side chain of replaced amino acids is rather crucial for developing molecular defects. (2) Defects in the ligand-binding pocket of the mutant receptors are driven primarily by loss/reduction (indirectly through structural changes in LBD induced by the mutations) of the electrostatic interaction formed by arginine 611 and threonine 739 of the receptor to glucocorticoid and a subsequent conformational mismatch (Figure 19B). (3) Defects of the AF-2 surface that reduce affinity to the LxxLL motif are caused mainly (also indirectly) by disruption of the electrostatic bonds to the non-core leucine residues of this peptide that determine the peptide’s specificity to GRa LBD (Figure 19C), as well as by reduced non-covalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent.

Figure 19.

Impact of pathologic GR point mutations to the molecular structure of GR LBD. A: Distribution of the pathologic GR point mutations in its LBD and their overall impact on the 3-dimensional LBD peptide backbone. Thickness and color of the overlaid C-traces of the GR mutant receptor LBDs and the wild type GR LBD indicate the areas of least (thin and blue) to most (thick and red) motion over the course of simulation. Locations and side chains of the mutated amino acids are indicated, whereas dexamethasone (shown with the white and red spheres of space-filling model) is located inside LBP. B: Alteration of the electrostatic bond formed by arginine (R) 611 and threonine (T) 739 of pathologic GR mutants to dexamethasone may largely explain the reduced affinity of many pathologic GR mutants to this steroid. The left panel demonstrates superimposed 3-dimensional interaction images of dexamethasone and the key residues of all pathologic GRa mutants. Among the key amino acids of pathologic mutants participating in interaction with dexamethasone, R611 is largely deviated in these mutant receptors, which underlies reduced/disappeared electrostatic interaction between this residue and the carbonyl oxygen at carbon-3 of dexamethasone. Q570 and N564 are omitted from these panels. Major changes observed in the electrostatic bond formed by R611 and T739 are indicated with a purple dotted circle. The right panel shows schematic molecular interaction between wild type GRa and dexamethasone. Purple and orange arrows indicate electrostatic and non-covalent bonds, respectively. DEX: dexamethasone. C: Defective non-covalent bonds formed between Q597, D590, K579 and R585 of the pathologic GRa mutants and N742, R746, D750 and D752 of the LxxLL peptide mainly explain reduced interaction of the mutant receptor AF-2s to this peptide. The panel demonstrates 3-dimensional image of the molecular interaction between the LXXLL peptide and key residues of the wild type GRa. The LxxLL peptide forms important electrostatic bonds with its non-core leucine residues (N742, R746, D750 and D752) against the receptor residues (Q597, D590, R585 and K579, respectively) as marked with purple dotted boxes. Pathologic GRa mutants demonstrate significant shift of the side chains of some of these receptor residues among which the side chain of R585 shows the most significant deviation (shown in square inserts). Modified from (89).

Viral Infection

HUMAN IMMUNODEFICIENCY VIRUS TYPE-1

Patients with the Acquired Immunodeficiency Syndrome (AIDS), which is caused by infection of the Human Immunodeficiency Virus type-1 (HIV-1), have several manifestations compatible with increased activity of GRa. They develop reduction of innate and Th1-directed cellular immunity, which is also seen in the conditions of glucocorticoid excess. Patients with AIDS often develop symptoms and signs that manifest in hypercortisolemic states, such as muscle wasting, myopathy, dyslipidemia and visceral obesity-related insulin resistance (462-466). Therefore, it is possible that some HIV-1-related factor(s) may modulate the function of GRa in patients with AIDS. Please see for more details the chapter on AIDS and the HPA Axis in the Adrenal Section of Endotext.

We have shown that one of the HIV-1 accessory proteins, Vpr, a 96-amino acid virion-associated protein with multiple functions (467,468), enhances GRa transactivation by functioning as a coactivator (469) (Figure 20). Indeed, Vpr contains a NR coactivator motif LxxLL at amino acids 64-68. This motif is used by host NR coactivators to bind NRs (80) (see Section ln ACTIONS OF GR, Mechanism of GRa-mediated Activation of Transcription). Similarly, through this motif, Vpr directly binds GRa and cooperatively enhances its activity on its responsive promoters along with host NR coactivators SRC-1 (p160-type protein, NCoA1) and p300/CBP (469). Vpr directly binds p300 at its C-terminal amino acids 2045-2191, where the p160 coactivators (NCoAs) also bind (470). Since Vpr circulates at detectable levels in HIV-1-infected individuals and is able to penetrate the cell membrane, its effects may be extended to cells not infected by HIV-1 (471,472). Indeed, extracellularly administered Vpr polypeptide regulates glucocorticoid-responsive genes, such as IL-12 p40, in the same way as the potent glucocorticoid, dexamethasone (473). In addition to regulating GRa activity, Vpr modulates the transcriptional activity of PPARb/d and PPARg, the NR family proteins important for fatty acid metabolism (474,475). Through modulating activities of GRa and the PPARs, Vpr appears to participate in the development of the characteristic AIDS-related lipodystrophy syndrome, which is quite prevalent among AIDS patients (476,477).

Figure 20.

Linearized Vpr, Tat, E1A, p300 and CtBP1 molecules and their mutual interaction domains. Vpr interacts with GR and several other NRs through its LxxLL motif located at amino acids 64 to 69. Binding sites of Vpr and p160-type HAT coactivators overlap with each other on p300. Since Vpr has a LxxLL motif similar to p160 coactivators, Vpr mimics host p160 coactivators and enhances GR transcriptional activity. Tat also binds both p300 and p160 coactivators. p300 facilitates attraction of many transcription factors, cofactors and general transcription complexes, and loosens the histone/DNA interaction through acetylation of the histone tails by its histone acetyltransferase (HAT) domain. E1A binds p300 at the latter’s C-terminal portion, while it physically interacts with the N-terminal portion of CtBP1 through its C-terminal end. The N-terminal portion of CtBP1 physically interacts with HDAC5 and Retinoblastoma protein (Rb), which have repressive activity on transcription. CtBP1 regulates its interaction to binding partners by sensing cellular NAD+ levels through its NAD+-binding domain. The HAT domain of p300 and the NAD+-binding domain of CtBP1 are indicated in grey. Modified from (478). CREB: CRE-binding protein, HAT: histone acetyltransferase, HDAC5: histone deacetylases 5, NF-B: nuclear factor-B, NAD: nicotinamide adenine dinucleotide, NR: nuclear hormone receptor, p/CAF: p300/CBP-associating factor, pTEFb: positive-acting transcription elongation factor b, Rb: retinoblastoma protein, SF-1: steroidogenic factor-1, STAT2: signal transducer and activator of transcription 2, TFIIB: transcription factor IIB.

Another HIV-1 accessory protein, Tat, which functions as a major transactivator of the HIV-1 long terminal repeat promoter (479) also potentiates GRa activity moderately by increasing accumulation of the positive transcription elongation factor b (pTEFb) (480-482) (Figure 20). Like Vpr, Tat readily penetrates the cell membranes (483) and may, therefore, modulate the transcriptional activity of GRa in the cells/tissues not infected by HIV-1.

Through Vpr and Tat, HIV-1 may facilitate the transcription of genes encoding its own proteins by directly stimulating viral proliferation. On the other hand, by enhancing transactivation of GRa and other NRs, these proteins may contribute to the viral proliferation possibly by suppressing the host immune system, while they participate in the development of several pathologic conditions associated with HIV-1 infection (480,484).

ADENOVIRUS

Adenoviruses cause illness of the respiratory system, such as common cold syndrome, pneumonia, croup and bronchitis, as well as illnesses of other organs, such as gastroenteritis, conjunctivitis and cystitis. They encode the E1A protein, which is expressed just after the infection and is necessary for the transcriptional regulation of the adenovirus-encoded genes (485). In addition to the viral genes, E1A regulates the transcriptional activity of a variety of host genes through interaction with the host transcriptional integrator p300 and its homologous molecule CBP (77,486) (Figure 20). In an in vitro system, E1A, in contrast to Vpr, blocks the actions of glucocorticoids on the transcriptional activity of genes, producing resistance to glucocorticoids (470).

E1A also interacts with the C-terminal tail-binding protein 1 (CtBP1), which functions as a transcriptional repressor for numerous transcription factors, by communicating with the class II HDACs and other inhibitory molecules like the retinoblastoma protein (Rb) (487) (Figure 20). E1A suppresses functions of p300/CBP and CtBP1 by binding to their functionally critical domains (77,487). Although there is no supportive clinical evidence, it is highly possible that adenovirus changes the peripheral action of glucocorticoids as well as of other bioactive molecules that activate NRs and directly regulates the transcriptional activity of their target genes, ultimately contributing to the pathologic states observed in adenoviral infection.

OTHER VIRUSES

We examined the impact of viral infection (murine cytomegalovirus: mCMV) on glucocorticoid-mediated modulation of gene expression in dendritic cells (488). Among 96 genes examined, the viral infection significantly enhanced dexamethasone-induced IL-10 expression. Activation of the toll-like receptors (TLRs) by the virus stimulates the extracellular signal-regulated kinase (ERK) 1/2, which in turn increases phosphorylation of the human GRa at serine 203, resulting in the enhancement of GRa transcriptional activity on the IL-10 gene promoter. Since IL-10 is a potent anti-inflammatory cytokine, it appears that the virus stimulates its own infection/propagation by enhancing GRa activity on this cytokine. Respiratory syncytial virus (RSV), which is one of the major causes of lower respiratory tract infection and hospital visits during infancy and childhood, is reported to repress the anti-inflammatory action of glucocorticoids through GRa (489-491).

ACKNOWLEDGEMENTS

This literary work was supported by the intramural fund of the Sidra Medical and Research Center to T. Kino.

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